JP2009268915A - Zero-order prolonged release coaxial implant - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a controlled release device which is biodegradable, that releases over a prolonged period of time, and that provides very controlled zero-order release kinetics. <P>SOLUTION: A coaxial implant has been developed using entirely biodegradable polymeric materials. The coaxial implant is a device having a core containing drug, surrounded by a semi-permeable membrane that controls the rate of release of material from the core. The device is formed by extrusion, using a pre-milling and extruding step to maximize uniformity of drug dispersion within the polymeric material. In one embodiment, the polymer is processed to yield a semi-crystalline polymer, rather than an amorphous polymer. The core containing the drug and the polymer membrane(s) can be the same or different polymer. The polymer can be the same or different composition and have the same or different molecular weights. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

(Background of the Invention)
The US Government has rights in the present invention by National Institute of Neurological Disorders and Stroke grant number 1R43NS39703-01.

  The present invention is generally in the field of long-term release devices for the delivery of formulations where there is a significant need for uniform zero-order release kinetics.

  The field of drug delivery has evolved over the past 30 years and is now ready to apply drug delivery with close precision over a long period of time, weeks to months after a single dose. . Long term controlled release has been achieved using several different devices. Examples include mini-implantable pumps for various drugs (especially chemotherapeutics and highly effective neuroactive agents), silicone tubes with controlled release holes at the ends for contraceptives, coaxial implants, transdermal Patches, and microencapsulated formulations are included. All of these have advantages and disadvantages. Minipumps are extremely accurate but are very expensive to manufacture. Mini-implant pumps, silicone tubes, and previously described coaxial implants must all be removed using invasive procedures once the drug has been delivered. A microencapsulated formulation can be formed using a biodegradable material as a whole, but its release characteristics are not controlled and can initially release a large amount of drug. This is problematic for some drugs and may have serious side effects if delivered in excess of the desired dosage or may be ineffective if not delivered at a sufficiently high dosage. Transdermal patches are useful only with a small number of drugs that pass through the skin and where accuracy of delivery is not essential.

  Cancer is diagnosed in more than 1 million Americans annually, and it is the fifth leading cause of death in the United States (approximately 1,400 people / day). The general progression of the disease often leads to chronic unsaved pain. The use of narcotic analgesics (including fentanyl and safentanil) is becoming more widely accepted as a selective treatment. Due to the potential development of tolerance and toxic side effects, long acting dosage forms that result in minimal initial mass release are required. As described above, several products are currently on the market including transdermal patches and implantable infusion systems. Transdermal patches can be used for outpatient treatment and have a duration of 3 days per dose. Intravenous and intrathecal infusions deliver narcotics more consistently and can be used over longer periods of time. Currently approved infusion products are generally bulky, require surgical procedures for implantation and removal, and are very expensive systems, using externally mounted or implanted pumps. Duros® safentanil (an osmotic pump designed for 100 day delivery of sufentanil) is currently undergoing clinical trials. This implant is much smaller, easier to administer and offers advantages over currently approved pumps, but requires removal at the end of the dosing period. This type of implant is described in WO 00/54745. Biodegradable implants can eliminate the need for removal, thereby providing additional benefits to the patient and eliminating the expense and discomfort of the surgical removal procedure.

An implant is described that can be made of a material comprising a biodegradable polymer. For example, U.S. Patent No. 6,057,031 to Shalati et al. Describes a controlled release implant (typically comprising a core of drug and water insoluble drug, and an outer polymer film that can be formed by coating an organic solvent with a water insoluble polymer and a water soluble pore former. Consists of fine particles or pellets). U.S. Patent No. 6,057,089 to Jawarowicz et al. Describes an implant made of a polymer whose outer coating is annealed to reduce porosity and avoid mass release. Both of these require expensive processing steps, increase costs, and may not be completely biodegradable.

US Pat. No. 4,666,704 US Patent Application Publication No. 2002/0037309

  Accordingly, it is an object of the present invention to provide a controlled release device that is biodegradable that releases over a long period of time and provides highly controlled zero order release kinetics.

  It is a further object of the present invention to provide a method for making such an implant that is cost effective, highly reproducible and efficient.

(Summary of the Invention)
Coaxial implants using polymeric materials that are totally biodegradable have been developed. As referred to herein, a coaxial implant is a drug (this is a solid or liquid drug) surrounded by a semi-permeable or microporous membrane that controls the release rate of the material from the core. A device having a core containing a drug in a solid or liquid matrix. As used herein, “semi-permeable” refers to a device in which the drug dissolves in and diffuses through the membrane polymer, and “microporous” refers to the drug in the membrane. A device that diffuses through the pores. The device can be formed by an extrusion process such as coaxial extrusion, or it can apply a coating to a preformed core containing the active ingredient, or an active loaded core to a preformed membrane material It can be formed by filling the formulation. In one embodiment, the polymer is processed to yield a semi-crystalline polymer, rather than an amorphous polymer. The core may contain the drug alone or mixed with another material such as a liquid carrier or biodegradable polymer. The core polymer (if used) and the polymer film (s) can be the same or different polymers. Polymers can be of the same or different molecular weight and of the same or different chemical structure (ie crystalline, semi-crystalline, or amorphous) with the same or different composition (ie both polycaprolactone, or both poly (lactide-co-). Glycolide) (of different monomer ratios), or polycaprolactone outside the core of poly (lactide). For devices with a dense polymer membrane, the core acts as a drug reservoir, which distributes from the core polymer to the membrane polymer to form a saturated solution of the drug at the interface between the core and the membrane. In general, hydrophobic polymers are used with hydrophobic drugs and hydrophilic polymers are used with hydrophilic drugs. When using drugs that are very hydrophilic, it may be preferable to use a microporous biodegradable polymer as the membrane polymer. In another embodiment, one of the core and the membrane is hydrophilic and the other is hydrophobic.

The present invention also provides the following items.
(Item 1)
A fully biodegradable coaxial implant comprising a core containing the active agent to be delivered and a rate controlling membrane, the implant fully degrading until all the active agent is released Not an implant.
(Item 2)
The implant of item 1, wherein the active agent is released over at least 30 days.
(Item 3)
The implant of item 1, wherein the core of the implant is formed from a biodegradable polymer having an active agent incorporated within the core.
(Item 4)
The implant according to item 1, wherein the membrane is a microporous membrane.
(Item 5)
The implant according to item 1, wherein the membrane is a semipermeable membrane.
(Item 6)
The implant of claim 1, wherein the core is formed by a dry blend of active agent and polymer followed by extrusion.
(Item 7)
The implant of item 1, wherein the core is formed by a double extrusion process.
(Item 8)
The implant according to item 1, wherein the core is a liquid.
(Item 9)
The implant of item 1, wherein the core is a pure drug.
(Item 10)
The implant according to item 1, wherein the polymer forming the film or core is semi-crystalline, crystalline or amorphous.
(Item 11)
The implant according to item 1, wherein the polymer forming the membrane and the polymer forming the core are the same polymer.
(Item 12)
The implant of item 1, wherein the active agent is released with zero order release kinetics.
(Item 13)
The implant of item 1, wherein the implant contains an active agent in or adjacent to the membrane.
(Item 14)
Polymeric implants, including monolithic implants or coaxial implants, for the delivery of anesthetic analgesics or antagonists thereof.
(Item 15)
15. Implant according to item 14, wherein the analgesic or antagonist is selected from the group consisting of sufentanil, fentanyl, naltrexone and naloxone.
(Item 16)
Item 15. The implant of item 14, wherein the polymer is biodegradable.
(Item 17)
Item 15. The implant of item 14, wherein the implant is a coaxial implant comprising a core containing the analgesic or antagonist and a rate controlling membrane.
(Item 18)
15. Implant according to item 14, which releases the analgesic or antagonist with a zero order release kinetics over a period of at least 30 days.
(Item 19)
15. Implant according to item 1 or 14, formed in a device selected from a matrix, prosthesis, implant or coating.
(Item 20)
20. An implant according to item 19, wherein the device is suitable for endovascular implantation.
(Item 21)
21. The implant of item 20, wherein the device contains an active agent selected from the group consisting of heparin, taxol and other drugs used in treating or preventing restenosis.
(Item 22)
20. Implant according to item 19, suitable for implantation into a body cavity.
(Item 23)
20. Implant according to item 19, suitable for transplantation adjacent to the plexus.
(Item 24)
15. Implant according to item 1 or 14, wherein the core composition further comprises concentric layers having different compositions.
(Item 25)
15. Implant according to item 1 or 14, wherein the core contains an excipient.
(Item 26)
Item 18. The implant according to Item 1 or 17, wherein the rate controlling membrane contains a pore forming agent.
(Item 27)
15. Implant according to item 1 or 14, wherein the implant contains a polymer selected from the group consisting of polyethylene glycol, polyhydroxy acid, caprolactone or copolymers thereof.
(Item 28)
The implant according to item 1, wherein the active agent is water-soluble.
(Item 29)
The implant according to item 1, wherein the active agent is a protein or a peptide.
(Item 30)
15. Implant according to item 1 or 14, wherein the implant is end-sealed.
(Item 31)
15. Implant according to item 1 or 14, wherein the implant is further processed after extrusion by stretching or annealing.
(Item 32)
The implant of item 1, wherein the core comprises a non-polymeric, non-aqueous liquid and an active agent.
(Item 33)
2. An implant according to item 1, formed by filling a preformed membrane with a liquid drug-containing formulation.
(Item 34)
The method of using an implant according to any one of items 1 to 33.
(Item 35)
A method of making a coaxial implant, the method comprising extruding an active agent and a polymer twice to form the core of the coaxial implant.
(Item 36)
36. The method of item 35, wherein the active agent and the polymer are dry blended prior to the first extrusion step.

FIG. 1 is a schematic representation of a coaxial die for making a coaxial implant. FIG. 2 is a graph (cumulative release (mg) vs. time (days)) of the effect of various film thicknesses on the release of naltrexone base from coaxial implants. FIG. 2a is a graph of an implant having a 10 wt% naltrexone core and a ratio of epicardial radius to intimal radius (r _o : r _i ) of 1.1, 1.4 and 1.9. FIG. 2 is a graph (cumulative release (mg) vs. time (days)) of the effect of various film thicknesses on the release of naltrexone base from coaxial implants. FIG. 2b is a graph of 1.1, 1.4 and 1.9 r _o : r _i implants with 30 wt% naltrexone core. FIG. 3 is a graph of the effect of core loading (5 mg and 15 mg) (cumulative release (mg) versus time (days)) on the release of naltrexone from coaxial polycaprolactone (“PCL”) implants. 4, respectively 1.27,1.45,1.59 and 1.83 _r o: for _{r i,} on the release of fentanyl from the coaxial PCL implants graph of the film thickness of the effect (cumulative release (mg ) Vs. time (days)). FIG. 5 shows the release of safentanil base from a coaxial implant containing 10% by weight of sufentanil in the core. FIG. 6 shows the release of sufentanil base from a coaxial implant containing 30% by weight of sufentanil in the core. FIG. 7 shows the release of cromolyn sodium from a coaxial implant with 30% by volume sodium chloride (pore former) / PCL membrane and 50% by weight cromolyn sodium / PCL core. r _o : r _i = 1.2. FIG. 8 shows the release of cromolyn sodium from a coaxial implant with 30% by volume sodium chloride (pore forming agent) / PCL membrane and a 50% by weight cromolyn sodium / PCL core. r _o : r _i = 1.30 and 1.40. FIG. 9 compares the cumulative release (mg) of cromolyn sodium from sealed and unsealed coaxial implants with a core of 50% by weight cromolyn / PCL with 30% by volume lactose / PCL membrane. r _o : r _i = 1.30 and 1.50. FIG. 10 shows cumulative release of cromolyn sodium (mg) from a coaxial implant with a core of 50 wt% cromolyn / PCL with a high density hydrophilic polymer membrane (polyethylene glycol 3000/90: 10 DL-polyethylene glycol membrane). ). r _o : r _i = 1.1, 1.4 and 1.7. FIG. 11 shows the release (mg) of cromolyn sodium from a coaxial implant with a hydrophobic PCL polymer membrane.

(Detailed description of the invention)
(1. Structure and composition of coaxial implant)
Methods for making fibrous implants for drug delivery are well known. For example, Cowsar and Dunn, Section 12 “Biodegradable and Nonbiodegradable Delivery Systems” pages 145-162; Gibson et al., Section 31 “Development of a Fibrous IUD Deliver”. the Delivery of Contraceptive Steroids to the Female Reproductive Tract, pages 125-146; Polymeric Materials in Medicine, C.I. G. See Dunn et al., “Fibrous Delivery Systems for Antimicrobial Agents,” pages 47-59, edited by Gebelin and Carraher (Plenum Publishing Corporation, 1985).

  There are three common methods for making fibers: wet spinning, dry spinning and melt spinning. Wet spinning involves extruding a polymer solution through an opening and into a non-solvent to solidify the polymer. In the dry spinning process, the polymer solution is forced through the openings and fed to a heated column that evaporates the solvent to form fibers. In melt spinning, the thermoplastic polymer is heated above its melting point, extruded through the openings, and allowed to cool to form fibers. Along with coaxial spinning, the drug is extruded as a fiber core (or referred to as an “outer cylinder”) simultaneously with the rate controlling polymer membrane. A typical coaxial spinneret consists of two concentric rings. The drug is pumped through the inner ring, either in pure form or dispersed within a polymeric or non-polymeric matrix, where the drug forms a core. The rate controlling polymer is pumped through the outer ring to form the outer cylinder. If both streams of material emerge from the spinneret, they solidify to form a concentric fiber or reservoir system. The rate at which the two materials are pumped into the coaxial spinneret determines the thickness of the outer membrane and the size of the fibers.

  The polymer or drug is liquefied either by melting or dissolving in a solvent for extrusion. A preferred method for the preparation of coaxial implants is melt extrusion, which uses two extruders to process the core formulation and the membrane material. The core formulation is fed to the central tube of the coaxial die and the membrane material is fed to the coaxial outer ring of the same die so that the membrane material is coated uniformly on the core as this material exits the die Form. The relative diameters of the core and membrane are controlled by die size, extrusion conditions, relative extrusion speed and relative take-off speed of the two extruders. In this way, the core diameter and film thickness can be controlled independently.

  Another way to prepare a coaxial implant is to first prepare the core formulation by a simple extrusion process and then form the membrane by surface treatment of this monolithic core. This surface treatment is accomplished by annealing the surface by exposing it to elevated temperatures or solvents for the polymer excipients so that the polymer forms a thin epidermis on its surface, and then as a rate controlling membrane Can be functionalized. The membrane may also be added by applying a coating of the membrane formulation by a solution coating process. A solution coating process can be used to apply additional layers of different compositions, thereby building a multi-layer coaxial implant.

  Yet another way to prepare a coaxial implant is to add this core formulation by first preparing the membrane as a hollow tube and then injecting the core formulation into the center of the tube. For example, core formulations are described in US Pat. No. 5,747,058, and US patent application Ser. No. 09 / 385,107, the entire contents of both of which are hereby incorporated by reference. Can be composed of drugs incorporated into a liquid matrix, such as a non-polymeric matrix, a water-insoluble matrix.

  Generally, the cross-section is formed in a circular shape, but the implant can also be prepared in any other cross-sectional shape (eg, oval, lobed, square, or triangular).

  The drug can be added to the formulation in various ways. If the core formulation includes a liquid carrier, the drug and carrier can be mixed to form a slurry. If the core formulation includes a polymer, the drug and polymer can be mixed by solvent mixing, dry mixing, or melt mixing. More uniform mixing can be obtained by extruding the drug-matrix twice. In a preferred embodiment, the core is formulated by dry mixing the drug and polymer, melting and extruding the mixture, and grinding the extrudate to form a feedstock for the second extrusion. . Drug loading in the core can range from about 0.1 to 80 wt% when either a liquid carrier or polymer is used in the core formulation, and as high as 100% when only the drug is used. It can be. A more preferred load is in the range of about 10 to about 60 wt%, and a most preferred load is in the range of about 20 to about 50 wt%.

  In some cases, the final implant is formed by cutting the core / membrane formulation to the appropriate length for the desired dose and sealing the exposed end of the core. For some applications, the initial loading dose may be desirable, by sealing only one of the exposed ends or none, so that there is a short period of higher release. It can be achieved for a specific drug. Several methods can be used to seal the end of the implant. If the implant contains a solid core, a hot knife so that it is heat sealed by coating with a solution of membrane polymer, or by applying a molten membrane polymer, or simply when the cut is made Or the implant can be sealed by cutting with a wire. If the implant includes a liquid core, the ends may be heat sealed or they may be sealed by placing a polymer plug within the lumen of the membrane formulation. If a polymer plug is used, it can be heat sealed to the membrane if desired.

  Coaxial implants can be prepared in various sizes depending on the total dose of drug and the intended method of administration. In a preferred embodiment, the total diameter is between 0.05 mm and 5.0 mm. For subcutaneous administration in humans, an overall diameter between 1.0 mm and 4.0 mm may be more preferred. The length of the coaxial implant is typically between about 0.3 cm and 10 cm. For subcutaneous implants, a more preferred length is between about 0.3 cm and 3.0 cm.

  The membrane formulation is selected to provide the required flux of drug (active agent) for a given size implant. For most practical applications, the membrane thickness is within about 2% to about 40% of the total diameter of the implant. It is preferred that the thickness of the membrane is between about 5% and about 30% of the total diameter. The membranes can be dense membranes that are not porous, or they have a pore size of about 1 to about 30 microns and a pore volume between about 5% and about 70% and are very porous. possible. The membrane may also contain an active ingredient at a lower load than that contained in the core, or may contain an active ingredient that is different from the active ingredient contained in the core. Regardless of whether the membrane is a dense membrane or a porous membrane, the desired permeability properties of the material need not necessarily be achieved during the initial extrusion or coating step. Downstream processing means can be used to achieve the final properties of the membrane. If a semicrystalline polymer is used in the membrane, the crystallinity can be controlled by the cooling rate and conditions. Properties can also be altered by drawing the extruded formulation. Stretching is generally accomplished by passing the material around two or more sets of godets, which operate at progressively higher speeds as the material passes further down the line. . This material can be passed through a heated oven between godets so that the temperature can be carefully controlled to further affect the crystallinity of the membrane. Stretching can also be used to control the final diameter of the material.

  Since the coaxial structures are prepared by a continuous extrusion process, they can be of any length convenient for operation. If the formulation is sufficiently flexible, it can be wound on a spool or in a coil and held in this way before cutting. Alternatively, the material can be collected, possibly as a few centimeters or shorter lengths of several meters, and held before cutting. It is also possible to cut this material to the final implant length when made using a flywheel type cutter located just downstream of the coaxial die.

(II. Process material)
(A. Polymer)
The process disclosed herein can be used to form coaxial implants from a variety of materials, preferably biocompatible and biodegradable polymers. As defined herein, biodegradable means that the polymer degrades or erodes in vivo to form smaller chemical species, where the degradation is, for example, It can result from enzymatic processes, chemical processes, and physical processes. The term “biocompatible” refers to a polymer and any degradation of that polymer that is non-toxic to the recipient and does not present any significant adverse or unfavorable effects on the recipient's body. Used herein to refer to a product. Examples of suitable biocompatible, biodegradable polymers include polyhydroxy acids (eg, poly (lactide), poly (glycolide), poly (lactide-co-glycolide), poly (lactic acid), poly (glycolic acid) And poly (lactic acid-co-glycolic acid)), polyanhydrides, polyorthoesters, polyetheresters, polyethylene glycols, polycaprolactones, polyesteramides, polyphosphazines, polycarbonates, polyamides, and copolymers and mixtures thereof. It is done. Preferred materials are polycaprolactone, poly (lactide), poly (glycolide), and copolymers thereof.

  Exemplary natural polymeric materials include polysaccharides and proteins.

(B. Solvent)
When the polymer and active agent are solvent mixed, the choice of solvent used in this process generally depends on the polymer and active agent selected and the particular means used for solvent removal. Organic solvents such as acetone, methyl ethyl ketone, tetrahydrofuran, ethyl lactate, ethyl acetate, dichloromethane, and ethyl acetate / alcohol mixtures are preferred for use with PLG and PCL.

(C. Activator)
Essentially any substrate or agent can be incorporated using the processes described herein. This substrate is preferably an active agent. As used herein, the term “active agent” refers to an in vivo therapeutic, prophylactic, or diagnostic property when administered to an animal, including a mammal such as a human. It refers to the drug you have. Examples of suitable therapeutic and / or prophylactic active agents include proteins (eg, hormones, antigens, and growth factors); nucleic acids (eg, antisense molecules); and small molecules (eg, antibiotics, steroids, congestion) Removal agents, neuroactive agents, anesthetics, sedatives), and antibodies (eg, antibodies that bind to growth hormone receptors including humanized antibodies), adjuvants, and combinations thereof. Examples of suitable diagnostic and / or therapeutic agents include radioactive isotopes and radiopaque agents.

  The active agent may be an organic molecule (eg, drug, peptide, protein, carbohydrate (including monosaccharides, oligosaccharides, and polysaccharides), nucleoprotein, mucoprotein, lipoprotein, synthetic polypeptide or protein, or protein Small molecules, glycoproteins, steroids, nucleic acids (DNA in any form, including cDNA, or RNA, or fragments thereof), nucleotides, nucleosides, oligonucleotides (including antisense oligonucleotides), genes, lipids, hormones, vitamins (Including vitamin C and vitamin E)) or combinations thereof.

Typical therapeutic active agents include: immunosuppressants, antioxidants, anesthetics, chemotherapeutic agents, steroids (including retinoids), hormones, antibiotics, antiviral agents, antifungal agents, antifungals Radioactive agents including proliferative agents, antihistamines, anticoagulants, antiphotoaging agents, melanotropic peptides, non-steroidal and steroidal anti-inflammatory compounds, antipsychotics, and UV absorbers Absorber. Other non-limiting examples of active agents include: anti-infectives (eg, nitrofurazone, sodium propionate), antibiotics (penicillin, tetracycline, oxytetracycline, chlorotetracycline, bacitracin, nystatin, streptomycin, Including neomycin, polymyxin, gramicidin, chloramphenicol, erythromycin, and azithromycin; sulfonamides (including sulfacetamide, sulfamethizole, sulfamethazine, sulfadiazine, sulfamerazine, and sulfisoxazole), and antiviral agents ( Including idoxuridine; antiallergic agents (eg, antazoline, metapyritene, chlorpheniramine, pyrilamine, Lofenpyridamine, hydrocortisone, cortisone, hydrocortisone acetate, dexamethasone, dexamethasone 21-phosphate, fluocinolone, triamcinolone, medorizone, prednisolone, prenizolone 21-sodium succinate, and prenizolone acetate (eg, ragweed pollen antigen), Hay fever pollen antigen, dust antigen and milk antigen); decongestants (eg, phenylephrine, naphazoline, and tetrahydrazoline); miotics and anticholinesterases (eg, pilocarpine, esperin salicylate, carbachol, diisopropylfluorophosphate, iodide) Phospholines, and deme potassium bromide); parasympatholytic agents (eg, atropine sulfate, cyclopentrate, homatropine, scopolamine) Sympathomimetics (eg, epinephrine); sedatives and hypnotics (eg, pentobarbital sodium, phenobarbital, secobarbital sodium, codeine, (a-bromoisovaleryl (a- bromoisovalentyl)) urea, carbomal); psychoactive agents (eg, 3- (2-aminopropyl) acetate indole, and 3- (2-aminobutyl) acetate indole); tranquilizers (eg, reserpine, chloropromarin ( chloropromline) and thiopropazate); androgenic steroids (eg methyl-testosterone and fluoresterone); estrogen (eg Eg, estrone, 17-β-estradiol, ethinylestradiol, and diethylstilbestrol; And 17-β-hydroxyprogesterone); humoral agents (eg, prostaglandins (eg, PGE ₁ , PGE ₂ and PGF ₂ )); antipyretics (eg, aspirin, sodium salicylate, and salicylamide); antispasmodics (eg, , Atropine, methanthelin, papaverine, and metoscopolamine bromide); antimalarials (eg, 4-aminoquinoline, 8-aminoquinoline, chloroquinone, o Antihistamines (eg, diphenhydramine, dimenhydrinate, tripelenamine, perphenazine, and chlorphenazine); cardioactive agents (eg, dibenzhydroflum) thiazide, flumethiazide, chlorothiazide, and aminotrate (Aminotrate), natural and synthetic bioactive peptides and bioactive proteins, including growth factors, cell adhesion factors, cytokines, and biological response modifiers.

  In one embodiment, the incorporated material is a vaccine and the delivered substrate is an antigen. Antigens can be delivered from cells, bacteria, or viral particles, or parts thereof. As defined herein, an antigen can be a protein, peptide, polysaccharide, glycoprotein, glycolipid, nucleic acid, or combinations thereof, which are animals (eg, mammals, birds, or fish). ) To induce an immunogenic response. This immunogenic response can be humoral mediated or cell mediated. In the event that the substance to which an immunogenic response is to be directed is poorly antigenic, the substance can be transferred to a carrier (e.g., , Albumin) or a hapten. Examples of preferred antigens include viral proteins (eg, influenza proteins, human immunodeficiency virus (HIV) proteins, and hepatitis A, hepatitis B or hepatitis C proteins), and bacterial proteins, lipopolysaccharides (eg, Gram-negative bacterial cell wall and Neisseria gonorrhea protein), and parvovirus.

  In a preferred embodiment, the delivered substrate is a drug (eg, a very powerful anesthetic analgesic) where the dosage should be carefully maintained within safe and effective levels. Examples include sufentanil and fentanyl. Naltrexone and other anesthetic analgesics are also preferred active agents such as interferon, cromolyn sodium and leuprolide acetate or other LHRH agonists or LHRH antagonists.

  The amount of active agent incorporated and the amount used in this process will vary depending on the particular active agent, the desired effect of the active agent at the planned release level, and the time period over which the agent is to be released.

  This process can be used to incorporate more than one active agent. The active agent can also be mixed with one or more excipients (eg, stabilizers) known in the art.

(D. Excipients and pore formers)
Suitable materials that can be added to the membrane polymer to achieve the desired porosity include sucrose, dextrose, sodium chloride, sorbitol, lactose, polyethylene glycol, mannitol, fructose, polyvinylpyrrolidone, or suitable combinations thereof. . These materials can also be mixed or incorporated into the core to provide fillers, can change the release rate, can increase water uptake, can control pH, and provide structural support And can provide other uses known to those skilled in the art.

(III. Method of use)
Coaxial implants are implanted using minimally invasive procedures at the site where release is desired. They can be implanted using trocars or catheters subcutaneously, intraperitoneally, intramuscularly and intraluminally (intravaginal, intrauterine, rectal, periodontal).

  Coaxial implants can be made as part of a matrix, implant, prosthesis or coating (eg, intravascular). Preferred active agents for use in the treatment of restenosis include heparin and taxol. These implants can also be used in the release of drugs near the plexus or under the bladder and near the pelvic plexus.

  Coaxial implants are designed so that the drug is released in a desired volume over a defined period of time. The coaxial implant is designed to disassemble after achieving release.

  The invention will be further understood with reference to the following non-limiting examples.

Example 1: Biodegradable coaxial implant for delivery of anesthetic analgesics
Coaxial extrusion has been evaluated as an efficient process for producing implants that can deliver drugs near zero order velocity. In this study, a biodegradable polymer, poly (ε-caprolactone) (PCL) was evaluated in an implant designed to deliver the drug for 30 days. This study was performed to determine the feasibility of developing a fully biodegradable reservoir implant that could deliver fentanyl or safentanil for 30 days.

(experimental method)
(material)
Naltrexone base (NTX), fentanyl base and safentanil base were prepared according to the procedure of Mallinckrodt, St. Obtained from Louis, Missouri. Poly (ε-caprolactone) (PCL) with an intrinsic viscosity of 1.31 dL / g in chloroform at 30 ° C. and 75:25 poly (DL-lactide-co-glycolide) with an intrinsic viscosity of 0.65 dL / g -Co-,-caprolactone) (DL-PLCL) to Birmingham
Polymers, Inc. , Birmingham, AL.

(Preparation of formulation)
All formulations were prepared by a melt-extrusion process using two Randcastle Microtruders and a coaxial die. The activator (NTX, fentanyl base and safentanyl base) and PCL were solvent blended using dichloromethane. After evaporation of most of the solvent, the mixture was vacuum dried and ground through a 1 mm screen using a Retsch Ultracentrifugal Mill. The ground material was further dried in a vacuum for at least 24 hours. Blends containing either 10% or 30% by weight of active agent were prepared.

  Coaxial rods containing NTX or fentanyl base were prepared by operating two extruders simultaneously. FIG. 1 shows a view of a coaxial die 10 used during extrusion. The activator / PCL blend was processed through the first extruder 12 and fed through the central opening 14 of the die 10 to form the implant core 10. Pure PCL was processed through the second extruder 18 and fed to the outside (coaxial ring 20 of the coaxial die 10) to form the membrane 22. Accordingly, the obtained coaxial rod is composed of the activator / PCL core 16 and the PCL ratio control film 22. The relative thickness of the membrane is controlled by adjusting the extrusion speed of the second extruder in relation to the speed of the first extruder. After extrusion, individual implants having a diameter of about 1.5 mm were cut to a length of 2.0 cm. The exposed ends were then sealed by coating the ends with a solution of PCL in dichloromethane.

  Coaxial rods containing sufentanil base were prepared by extruding a monolithic rod containing a sufentanil / polymer blend and cutting the rod to a length with the desired amount of safentanil. The rod was coated by dipping in a solution of polymer dissolved in dichlorometa. Individual coatings were applied until the desired film thickness was achieved.

(Naltrexone content assay)
The active ingredient of individual naltrexone implants was determined by dissolving the implants in ethyl acetate, diluting the solution with HPLC mobile phase, and analyzing the resulting extract by HPLC.

(In vitro dissolution)
Active agent release was measured in vitro using a simple dissolution test. Individual naltrexone and sufentanil implants in 2-oz amber storage bottles with 10 mL buffer (phosphate buffered saline with 0.05% sodium azide, pH 7.4) Placed and incubated at 37 ° C. Periodically, a known volume of buffer was removed and replaced with fresh buffer. The concentration of drug in the buffer of each sample was measured by HPLC.

  Individual sufentanil implants were placed in 8-oz amber storage bottles containing 20 mL of buffer. After 1 hour, the total volume of the buffer was increased to 70 ml. At each sampling, an aliquot of 10 ml buffer was removed and replaced with 10 mL fresh buffer. The sufentanil concentration of each sample was measured by HPLC.

(Results and discussion)
Several experiments were conducted to determine the optimal conditions for coaxial extrusion. Table 1 shows the process conditions used during NTX coaxial extrusion for two Randcastle Extruders.

  (Table 1: Coaxial extrusion molding conditions)

図２は、種々のインプラント処方物に対する、ナルトレキソン塩基のｍｇ／日での放出を示し、この種々の処方物は、モノリシックなコアおよび異なる膜厚を有するコーティングされたロッドを含む。コアおよび膜厚を、インプラントの内半径（ｒ_ｉ）および外半径（ｒ_ｏ）を測定することによって決定した。期待されるように、膜はインプラントからのＮＴＸ塩基の放出速度を制御する。ポリマー膜が厚いほど、同軸インプラントからのナルトレキソン塩基の放出は遅くなる。

FIG. 2 shows the release of naltrexone base in mg / day for various implant formulations, which include a monolithic core and coated rods with different film thicknesses. The core and film thickness were determined by measuring the inner radius (r _i ) and outer radius (r _o ) of the implant. As expected, the membrane controls the release rate of NTX base from the implant. The thicker the polymer film, the slower the release of naltrexone base from the coaxial implant.

3, 1: 1 _r o: shows a comparison between the core loading for the implant with a _{r i.} Lower loaded implants show a gradual decay in NTX release rate. This rate decay is partly due to the low initial concentration of the drug relative to the saturated solubility of the drug in the core polymer. As the drug is released and the concentration of active in the core is below saturation, the zero order release profile is not maintained. However, at the highest core loading, saturation and zero order release profiles can be maintained for longer durations.

  FIG. 4 shows the release of fentanyl base from a coaxial implant containing 10 wt% fentanyl base in the core. As in the NTX implant, as the concentration in the core falls below saturation, the release of fentanyl is of the first order.

  Figures 5 and 6 show the release of safentanil base from a coaxial implant containing 10 wt% safentanil base and 30 wt% safentanil base, respectively, in the core.

Example 2: Biodegradable coaxial implant for the delivery of cromolyn sodium with sodium chloride as pore-forming agent in the membrane
The core materials (50:50 (w / w) cromolyn sodium (chromoline) and PCL (having an intrinsic viscosity of 0.67 dL / g in chloroform at 30 ° C.)) are blended together, formulated, and It was ground through a 1 mm screen using a Retsch Ultracentrifugal Mill. Membrane material (30% (v / v) sodium chloride (NaCl) and PCL (having an intrinsic viscosity of 1.37 dL / g in chloroform at 30 ° C.)), blended, and ground as well as the core material It was. The core material and membrane material were dried under vacuum for a minimum of 16 hours.

  Coaxial rods were produced by operating two Randcastle extruders simultaneously. Core material (Cromolyn / PCL) was fed through the central opening of the die in the first extruder to mold the core of the implant. Membrane material (NaCl / PCL) was fed through a second extruder through the outer ring of the coaxial die to form the membrane. Individual implants with a diameter of about 2 mm were cut to a length of 2 cm. The exposed end was sealed with the same polymer as the membrane.

  The release of cromolyn was determined in vitro using a simple dissolution test. Individual implants were placed in a 4-oz jar with 40 mL buffer (phosphate buffered saline with 0.05% sodium azide, pH 7.4) and incubated at 37 ° C. . Periodically, aliquots of buffer were removed and replaced with fresh buffer. The cromolyn concentration in each sample was determined by HPLC.

  FIG. 7 shows the release of cromolyn from a coaxial implant in which NaCl is used as the pore former.

Example 3: Biodegradable coaxial implant for the delivery of cromolyn sodium with sodium chloride as pore-forming agent in the membrane
Core material (Cromolyn sodium (Cromolyn) ground and formulated with PCL having an intrinsic viscosity of 0.67 dL / g in chloroform at 30 ° C. (50:50 (weight / weight))) and membrane material (30 ° C. Of cromolyn (30% (volume / volume)), ground and formulated with PCL having an intrinsic viscosity of 1.37 dL / g in chloroform, was processed and analyzed as in Example 2. FIG. 8 shows the release of cromolyn from a coaxial implant in which this cromolyn is used as a pore former. As expected, the membrane controls the rate at which cromolyn is released. Thicker polymer membranes cause slower cromolyn release.

Example 4: Biodegradable coaxial implant for delivery of cromolyn sodium using lactose as a pore former in the membrane
Core material (Cromolyn sodium (Cromolyn) ground and compounded with PCL having an intrinsic viscosity of 0.67 dL / g in chloroform at 30 ° C.) (50:50 (weight / weight)) and membrane material (30 ° C. Lactose ground and formulated with PCL having an intrinsic viscosity of 1.37 dL / g in chloroform (30% (volume / volume))) was processed and analyzed as in Example 2. FIG. The graph shows the release of cromolyn from a coaxial implant and the graph compares the release from a sealed implant with the release of an unsealed implant, as expected, an unsealed implant is better than a sealed one. Fast release.

Example 5: Biodegradable coaxial implant for delivery of cromolyn sodium from dense PEG3K / 90: 10 DL-PLG polymer membrane
Core material (Cromolyn sodium (Cromolyn) ground and formulated with PCL having an intrinsic viscosity of 0.67 dL / g in chloroform at 30 ° C. (50:50 (weight / weight))) and membrane material (30 ° C. Of PEG3K / 90: 10 DL-PLG) with an intrinsic viscosity of 0.89 dL / g) in chloroform and analyzed as in Example 2.

  FIG. 10 shows the release of cromolyn from a coaxial implant with a dense hydrophilic polymer membrane.

Example 6: Biodegradable coaxial implant for delivery of cromolyn sodium from dense PCL membrane
Core material (Cromolyn sodium (Cromolyn) ground and formulated with PCL having an intrinsic viscosity of 0.67 dL / g in chloroform at 30 ° C. (50:50 (weight / weight))) and membrane material (30 ° C. PCL having an intrinsic viscosity of 1.37 dL / g in chloroform, and processed as in Example 2.

  FIG. 11 shows the release of cromolyn from a coaxial implant with a dense hydrophilic polymer membrane.

Example 7: Biodegradable coaxial implant for protein delivery
Using nitrogen gas as the core feed, a mixture containing 30% by volume NaCl in PCL was extruded through the outer ring of the coaxial die as described above to form a tubing having an overall diameter of about 3 mm. An implant containing α-interferon was prepared from the tubing by filling a short length of tubing with a suspension containing 20 mg α-interferon in sucrose acetate isobutyrate (SAIB) and sealing the end of the tube.

  When incubated in phosphate buffered saline, the implant released interferon for several days.

Claims (1)

Invention described in the specification.

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